Extrahepatische Cholestase induziert Leberzellschädigung durch LFA-1 (lymphocyte function antigen-1) -abhängige Leukozytenrekrutierung

Abstract

Background: Obstructive jaundice is associated with a pro-inflammatory response in the liver, resulting in leukocyte accumulation and hepatocellular damage. However, the adhesive mechanisms behind cholestasis-induced leukocyte recruitment in the liver are not known. In the present study, we evaluated the role of lymphocyte function antigen-1 (LFA-1) in cholestatic liver injury. Methods: C57BL/6 mice underwent bile duct ligation (BDL) for 12 hours. Mice were pre-treated with an anti- LFA-1 antibody or a control antibody. Subsequently, hepatic accumulation of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Hepatocellular damage was monitored by serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were determined by ELISA. Results: BDL provoked a recruitment of leukocytes and significant liver damage indicated by sinusoidal perfusion failure and increased levels of liver enzymes. Circulating neutrophils expressed higher levels of LFA-1 and inhibition of LFA-1 significantly reduced ALT and AST levels in cholestatic mice. Notably, immunoneutralization of LFA-1 reduced BDL-induced leukocyte adhesion in postsinusoidal venules whereas leukocyte rolling and sinusoidal accumulation were not changed. Moreover, blocking LFA-1 function restored sinusoidal blood perfusion in cholestatic animals. Conclusion: These findings demonstrate an important role of LFA-1 in supporting cholestasis-induced leukocyte recruitment in the liver. Moreover, blocking LFA-1 function markedly reduced liver damage and microvascular perfusion in bile duct ligated animals. Thus, our novel data suggest that targeting LFA-1 may help to protect against pathological inflammation and liver damage in cholestatic liver diseases.